Clinical Challenges: Combination Therapy for Osteoporosis

Studies show a benefit in high-risk patients

AUSTIN, Texas -- While monotherapy, generally with bisphosphonates or other antiresorptive agents, is generally standard of care for osteoporosis, significant strides have been made in combination therapy -- particularly by pairing an anabolic drug with an antiresorptive agent, one researcher argued.

"In some ways, osteoporosis is very different from other chronic diseases, such as diabetes and hypertension, that use agents from more than one class," Benjamin Z. Leder, MD, chair of the American Society for Bone and Mineral Research (ASBMR) Professional Practice Committee and an endocrinologist at Massachusetts General Hospital in Boston, told MedPage Today. "To treat osteoporosis, historically we use one drug at a time at a single dose and transition from one to the other without a lot of thought about combining the two."

But over the past 10 years, that school of thought is beginning to change. While researchers have already studied the effects of combining antiresorptive agents with each other "20 to 30 years ago," Leder pointed to recent interest in combining an anabolic agent with an antiresorptive agent.

In 2013, Leder's team published a study that found that combining the anabolic agent teriparatide (Forteo) with the antiresorptive agent denosumab (Prolia) was linked with greater bone mineral density compared with using a single therapy.

But Leder added that there have been a number of barriers to wider uptake of combination therapy. The first is that there have yet to be fracture studies done for the treatment. Leder said that studies have used other surrogate endpoints, such as bone density, bone quality, bone microarchitecture and bone strength, and combination therapy improved these endpoints, but there have yet to be studies to prove that this therapy can better reduce the incidence of fracture in high-risk patients.

"Those studies are done in thousands of patients over many years, and outside of funding from a specific pharma company, they are hard to do," Leder said.

He voiced his hope for a fracture efficacy study that would compare anabolic and antiresorptive agents with the most common antiresorptive agent. "Hopefully the study will be done either from industry or from the NIH," he added.

In addition to combination therapy, the sequence of the therapy appears to make a difference in the outcome. Even if the drugs are used in combination, Leder said it is becoming "increasingly clear" from the research that one should start patients on an anabolic agent first, followed by an antiresorptive agent rather than giving the drugs in the opposite order.

Leder's team published an additional article in The Lancet in 2015, which found that patients who switched from the anabolic agent teriparatide to the antiresorptive agent denosumab had an increase in bone mineral density, but if patients switched from denosumab to teriparatide, the effects of the treatment were blunted. A 2016 editorial in the Journal of Bone and Mineral Research also argued that "the order matters" in osteoporosis patients receiving this type of combination therapy.

Barriers to Adoption

But Leder cited a couple of barriers to this type of treatment being more widely adopted: First, different medical societies have different guidelines for the treatment of osteoporosis. In addition to the lack of fracture studies, Leder said, "the data is fairly recent," on combination therapy.

In fact, the most recent guidelines from the American Association of Clinical Endocrinologists (AACE) on the diagnosis and treatment of osteoporosis in postmenopausal women explicitly state that "until the effect of combination therapy on fracture risk is demonstrated, AACE does not recommend concomitant use of these agents for prevention or treatment of postmenopausal osteoporosis."

Moreover, the most recent guidelines from the American College of Physicians (ACP) "didn't discuss sequence therapy or combination therapy or anabolic therapy at all," Leder said.

"It would help a lot if it was incorporated into the guidelines," he argued. "I would expect it, as the guidelines continue to evolve."

The second barrier to combination therapy is the way that payers mandate that the drugs are used. Leder said that insurance will not let clinicians use an anabolic agent to treat osteoporosis patients first -- that it will be allowed only if bisphosphonate therapy has not worked well.

Leder emphasized that most patients with osteoporosis can be treated with a single drug, but that those with the highest risk of fracture, such as patients with a metabolic abnormality, would benefit from combination therapy. His hope, he said, is that clinical trials will continue to examine different forms of combination therapy.

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